Melatonin, 5-methoxy-N-actyltryptamine, is a major hormone of the pineal gland. The synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senescence. The rhythm appears to be the result of both endogenous mechanisms and environmental cues, most notably, the exposure of mammals to light, which inhibits melatonin synthesis and secretion. Melatonin is thought to be the hormonal mediator of photoperiodic changes. Evidence suggests that melatonin is involved in the regulation of circadian rhythms and a variety of neural and endocrine functions. Melatonin has been implicated in a number of human disorders, particularly those relating to chronobiologic abnormalities. Researchers have suggested administering melatonin to alleviate or prevent disturbances in circadian rhythms caused by the rapid crossing of time zones, e.g., jet lag, or changes in work shifts from night to day. See European Patent Application 0 126 630, by Short et al.
Melatonin analogues have been studied for their effects on the reproductive system, specifically antigonadal activity and inhibition of release of luteinizing hormone (LH); see Flaugh et al., Journal of Medicinal Chemistry, (1979) 22:63-69.
Frohn et al., Life Sciences, Vol. 27, pp. 2043-2046, Pergamon Press, and Clemens et al., J. Neural Transm., (1986) [suppl.] 21:451-459, disclose melatonin analogues wherein the activity of such analogues is related to structure. Analogues with improved metabolic stability, e.g., 2-methyl-6,7-dichloromelatonin, are disclosed.
Heward and Hadley, (1975), Life Sci., 17:1167-1168, reported in-vitro method for measuring the melatonin response of various indoleamines, including melatonin and 5-methoxy-N-acetyltryptamine, by frog skin lightening. Of the compounds disclosed in this article, only N-acetyltryptamine and N-acetylserotonin were reported to have "melatonin blocking activity".
Dubocovich, Eur. J. Pharmacol., 105:193-194, 1984, also reported that N-acetyltryptamine competitively antagonized the inhibitory effect of melatonin in the chicken retina, thus demonstrating melatonin blocking activity by a more sensitive in-vitro method than utilized by Heward and Hadley.
In Cattanoch, et al., J. Chem Soc. c(10) 1235-43 (1968) a series of tetrahydro-1H-pyrido [4,3-b] indoles were prepared and examined for their ability to block the pharmacological actions of seratonin. The 2-acetyl derivatives of 8-chloro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole was synthesized but never tested for any type of physiological activity. Also see ibid, c(2) 359-66, (1971) for related tetrahydroxyamide [3,4-a] compounds.
Several studies have suggested that the pineal gland may influence the development and growth of mammary tumors in addition to hormone-responsive reproductive tissue. For example, melatonin administration has been shown to inhibit, while pineolectomy generally stimulates mammary carcinogenesis. Melatonin has, in fact, been studied with an aim to prove that it retards hormone responsive breast cancer growth by directly inhibiting all proliferation. See Hill, et al., Cancer Research 40 6121-26, (1988).
It is of continuing interest to identify compounds which can inhibit abnormal cell proliferation, while minimizing side effects.